A phase 2 study of MK-5442, a calcium-sensing receptor antagonist, in postmenopausal women with osteoporosis after long-term use of oral bisphosphonates.

Abstract

UNLABELLED:

In women with osteoporosis treated with alendronate for >12 months and oral bisphosphonates for >3 of the last 4 years, switching to MK-5442, a calcium receptor antagonist, stimulated endogenous parathyroid hormone (PTH) secretion and increased bone turnover marker levels, but produced a decline in bone mineral density (BMD) at all sites.

INTRODUCTION:

This study assessed the effects of switching from long-term oral bisphosphonate therapy to the calcium-sensing receptor antagonist MK-5442 on BMD and bone turnover markers (BTMs) in post-menopausal women with osteoporosis.

METHODS:

This randomized, active and placebo-controlled, dose-ranging study enrolled 526 postmenopausal women, who had taken alendronate (ALN) for ≥12 months preceding the trial and any oral bisphosphonate for ≥3 of the preceding 4 years and had spine or hip BMD T-scores ≤-2.5 or ≤-1.5 with ≥1 prior fragility fracture. Women were randomized to continue ALN 70 mg weekly or switch to MK-5442 (5, 7.5, 10, or 15 mg daily) or placebo.

RESULTS:

Switching from ALN to MK-5442 produced a dose-dependent parathyroid hormone (PTH) pulse of threefold to sixfold above baseline at 1 h, with PTH levels that remained twofold to threefold above baseline at 4 h and returned to baseline by 24 h. Switching to MK-5442 or placebo increased BTM levels compared to baseline within 3 months and MK-5442 10 mg increased BTM levels compared to placebo by 6 months. With all MK-5442 doses and placebo, spine and hip BMD declined from baseline, and at 12 months, BMD levels were below those who continued ALN (all groups P < 0.05 vs ALN). There was also a dose-dependent increase in the incidence of hypercalcemia with MK-5442.

CONCLUSION:

Switching from ALN to MK-5442 resulted in a pulsatile increase in PTH and increases in BTMs, but a decline in BMD compared with continued ALN. MK-5442 is not a viable option for the treatment of osteoporosis.

• Authors: F Cosman, N Gilchrist, M McClung, J Foldes, T de Villiers, A Santora, A Leung, S Samanta, N Heyden, J P McGinnis 2nd, E Rosenberg, A E Denker
• Journal: Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA (Osteoporos Int) Vol. 27 Issue 1 Pg. 377-86 (Jan 2016) ISSN: 1433-2965 [Electronic] England
• PMID: 26556736 (Publication Type: Clinical Trial, Phase II, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Benzoates
• Biomarkers
• Bone Density Conservation Agents
• Diphosphonates
• JTT 305
• Parathyroid Hormone
• Propanolamines
• Receptors, Calcium-Sensing

Topics

• Administration, Oral
• Aged
• Benzoates (therapeutic use)
• Biomarkers (blood)
• Bone Density (drug effects)
• Bone Density Conservation Agents (therapeutic use)
• Diphosphonates (administration & dosage, therapeutic use)
• Dose-Response Relationship, Drug
• Double-Blind Method
• Drug Administration Schedule
• Female
• Femur Neck (physiopathology)
• Hip Joint (physiopathology)
• Humans
• Lumbar Vertebrae (physiopathology)
• Middle Aged
• Osteoporosis, Postmenopausal (drug therapy, physiopathology)
• Parathyroid Hormone (blood)
• Propanolamines (therapeutic use)
• Receptors, Calcium-Sensing (antagonists & inhibitors)